Abstract
BackgroundSessile serrated adenomas/polyps (SSA/Ps) may account for 20–30% of colon cancers. Although large SSA/Ps are generally recognized phenotypically, small (<1 cm) or dysplastic SSA/Ps are difficult to differentiate from hyperplastic or small adenomatous polyps by endoscopy and histopathology. Our aim was to define the comprehensive gene expression phenotype of SSA/Ps to better define this cancer precursor.ResultsRNA sequencing was performed on 5′ capped RNA from seven SSA/Ps collected from patients with the serrated polyposis syndrome (SPS) versus eight controls. Highly expressed genes were analyzed by qPCR in additional SSA/Ps, adenomas and controls. The cellular localization and level of gene products were examined by immunohistochemistry in syndromic and sporadic SSA/Ps, adenomatous and hyperplastic polyps and controls. We identified 1,294 differentially expressed annotated genes, with 106 increased ≥10-fold, in SSA/Ps compared to controls. Comparing these genes with an array dataset for adenomatous polyps identified 30 protein coding genes uniquely expressed ≥10-fold in SSA/Ps. Biological pathways altered in SSA/Ps included mucosal integrity, cell adhesion, and cell development. Marked increased expression of MUC17, the cell junction protein genes VSIG1 and GJB5, and the antiapoptotic gene REG4 were found in SSA/Ps, relative to controls and adenomas, were verified by qPCR analysis of additional SSA/Ps (n = 21) and adenomas (n = 10). Immunohistochemical staining of syndromic (n≥11) and sporadic SSA/Ps (n≥17), adenomatous (n≥13) and hyperplastic (n≥10) polyps plus controls (n≥16) identified unique expression patterns for VSIG1 and MUC17 in SSA/Ps.ConclusionA subset of genes and pathways are uniquely increased in SSA/Ps, compared to adenomatous polyps, thus supporting the concept that cancer develops by different pathways in these phenotypically distinct polyps with markedly different gene expression profiles. Immunostaining for a subset of these genes differentiates both syndromic and sporadic SSA/Ps from adenomatous and hyperplastic polyps.
Highlights
Colon cancer is the second leading cause of cancer deaths in the United States, with more than 100,000 new cases diagnosed yearly [1,2]
Biopsy specimens were placed in RNAlater (Invitrogen) immediately following collection and stored at 4uC overnight prior to total RNA isolation the following day. cDNA from the same sessile serrated adenomas/polyps (SSA/Ps) of serrated polyposis syndrome (SPS) patients used for RNA analysis and from hyperplastic polyps (HPs, n = 10, 3– 9 mm diameter) prospectively collected from the left colon of five SPS patients were used for BRAF mutation analysis
Gene Expression Analysis Right-sided SSA/Ps were collected from eleven patients with SPS (Table 1, Table S2 in File S1, Figure 1) and RNA isolated for RNA sequencing (RNA-seq) and qPCR analysis
Summary
Colon cancer is the second leading cause of cancer deaths in the United States, with more than 100,000 new cases diagnosed yearly [1,2]. Recent studies provide evidence that a subset of serrated polyps, sessile serrated adenomas/polyps (SSA/Ps), which remain inadequately defined but generally have a flat phenotype with a mucus cap, right colonic predominance and a distinctive serrated morphology, may account for 20–30% of colon cancers [3,4,5,6,7,8]. The Serrated Polyposis Syndrome (SPS) is an exaggerated serrated polyp phenotype exhibiting multiple SSA/Ps with a high risk of colon cancer [3,4]. Two studies of at least 100 patients with SPS indicated a 25%–42% increased risk for colon cancer [10,11]. An increased risk of colon cancer in relatives of patients with SPS has been suggested [10], the great majority of SPS cases do not appear to be hereditary. Our aim was to define the comprehensive gene expression phenotype of SSA/Ps to better define this cancer precursor
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